Water stabilized medicinal aerosol formulation

ABSTRACT

This invention relates to a medicinal aerosol suspension formulation and more particularly, to a medicinal aerosol formulation containing a particulate drug or a combination of at least two particulate drugs, a propellant and a stabilizing agent comprising a water addition.

RELATED APPLICATIONS

[0001] This application is a continuation-in-part of application U.S.Ser. No. 09/619,183, filed on Jul. 19, 2000, which in turn is acontinuation-in-part of application U.S. Ser. No. 09/209,228, filed Dec.10, 1998, now U.S. Pat. No. 6,261,539 all of which are incorporatedhereinto by reference in their entirety.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This invention relates to a medicinal aerosol formulation, andmore particularly, to a medicinal aerosol formulation comprising astabilizer comprising a water addition.

[0004] 2. Description of the Related Art

[0005] Delivery of drugs to the lung by way of inhalation is animportant means of treating a variety of conditions, including suchcommon local conditions as bronchial asthma and chronic obstructivepulmonary disease and some systemic conditions, including hormonereplacement, pain management, cystic fibrosis, etc. Steroids, β2agonists, anticholinergic agents, non-steroidal antiinflammatory agents,proteins and polypeptides are among the drugs that are administered tothe lung for such purposes. Such drugs are commonly administered to thelung in the form of an aerosol of particles of respirable size (lessthan about 10 μm in diameter). The aerosol formulation can be presentedas a liquid or a dry powder. In order to assure proper particle size ina liquid aerosol, as a suspension, particles can be prepared inrespirable size and then incorporated into the suspension formulationcontaining a propellant. Alternatively, formulations can be prepared insolution form in order to avoid the concern for proper particle size inthe formulation. Solution formulations must nevertheless be dispensed ina manner that produces particles or droplets of respirable size.

[0006] Once prepared an aerosol formulation is filled into an aerosolcanister equipped with a metered dose valve. In the hands of the patientthe formulation is dispensed via an actuator adapted to direct the dosefrom the valve to the patient.

[0007] It is important that an aerosol formulation be stable such thatthe pressurized dose discharged from the metered dose valve isreproducible. Rapid creaming, settling, or flocculation after agitationare common sources of dose irreproducibility in suspension formulations.This is especially true where a binary aerosol formulation containingonly medicament and propellant, e.g. 1,1,1,2-tetrafluoroethane, isemployed or where such formulation contains small amounts of surfactantas well. Sticking of the valve also can cause dose irreproducibility. Inorder to overcome these problems aerosol formulations often containsurfactants, which serve as suspending aids to stabilize the suspensionfor a time sufficient to allow for reproducible dosing. Certainsurfactants also function as lubricants to lubricate the valve to assuresmooth actuation. Myriad materials are known and disclosed for use asdispersing aids in aerosol formulations. Suitability of materials,however, is dependent on the particular drug and the propellant or classof propellant used in the formulation.

[0008] It is sometimes difficult to dissolve sufficient quantities ofconventional surfactants in hydrofluorocarbon (HFC) propellants such asHFC-134a and HFC-227. Cosolvents, such as ethanol, have been used toovercome this problem, as described in U.S. Pat. No. 5,225,183. Analternative approach that avoids cosolvents involves materials that aresoluble in hydrofluorocarbon propellants and are said to be effectivesurfactants or dispersing aids in an aerosol formulation. Among suchmaterials are certain fluorinated surfactants and certainpolyethyoxysurfactants.

[0009] It is known in the art that the presence of water in conventionalaerosol formulations often result in a number of potential problems,e.g. stability of the formulation, erratic dose delivery, and, in somecases free radical reactions in the propellant. Therefore, it hasgenerally been accepted that these preparations should be maintainedsubstantially free of water. The rigorous exclusion of atmosphericmoisture during both the manufacture and storage of such formulations,referred to as “developed” or “nascent” formulation water, increases thedifficulties of preparing satisfactory stable aerosols containing thedrug and raises the overall cost of the final product, especially when amoisture barrier, e.g. foil pouching, is included as a secondarypackage.

[0010] An exception had been found for beclomethasone dipropionatemonohydrate. It has been reported that a formulation of this particularmedicament combined with an amount of water in addition to its water ofhydration is stable. In this regard, reference is made to U.S. Pat. No.5,695,744 (“NEALE”).

[0011] U.S. Pat. No. 5,695,744 (NEALE) relates to aerosol formulationsfor the administration of beclomethasone dipropionate monohydrate byinhalation, which comprises at least 0.015% by weight of water inaddition to the water of crystallization associated with the monohydrateform of the medicament in order to preserve the solvate form of the drugas well its particle size properties. It is particularly claimed thatthe formulation must comprise at least 0.015% by weight of theformulation of water in addition to the water of crystallizationassociated with said monohydrate whereby said at least 0.015% waterstabilizes the particle size of said beclomethasone dipropionatemonohydrate particles. It is noted that other work by the NEALE in U.S.Pat. No. 5,833,950 [Aerosol formulations containing beclomethasonedipropionate-1, 1, 1, 2-tetrafluoroethane solvate] suggests that, forthese beclomethasone dipropionate formulations to be stable inpropellant fluids, notably—1,1,1,2-tetrafluoroethane, the medicamentmust be in fine crystalline solvate form, and preferably, that theformulations of the invention are substantially free of other potentialsolvating species such as chlorofluorocarbons, ethyl acetate, alkanes,ethers, alcohols and water. NEALE most importantly suggest that, inparticular, the formulations of the solvate of the beclomethasonecompound must be substantially free of water, for example containingless than 250 ppm, preferably less than 200 ppm, more preferably lessthan 100 ppm, for example less than 50 ppm water (U.S. Pat. No.5,833,950, NEALE).

[0012] NEALE in these patents, discloses aerosol formulation technologyfor beclomethasone dipropionate monohydrate alone that substantiallymaintains intact the particular solvate form as well as its crystalshape, morphology, and other surface enegertic properties in theformulation. It is understood then that maintenance of the solvate formof the particulate medicament, together with its particle sizeproperties, is the primary and only technically juslifiable purpose ofthe NEALE patents.

[0013] What has not been appreciated, however, is that despite allefforts an amount of water develops in medicinal aerosol formulationsduring processing of such formulations which can not be eliminated andis always present (“developed” or “nascent” formulation water). Mostsurprising and unexpected is that such unstable formulations, containingnascent formulation water, can be and are stabilized by the presence ofa concentration of water added in addition to the nascent or developedformulation water which stabilizes such medicament formulations.

SUMMARY OF THE INVENTION

[0014] It has surprisingly been found that novel medicinal aerosolformulations can be obtained without the use of either cosolvents, suchas ethanol, or surfactants, such as sorbitan trioleate which are addedto a binary aerosol formulation. Stable medicinal aerosol suspensionformulations are obtained by the use of a water addition.

DETAILED DESCRIPTION OF THE INVENTION

[0015] This invention involves a stable suspension aerosol formulationsuitable for pressurized delivery which comprises (1) a particulatemedicament or drug or combination of at least two medicaments or drugs,(2) a suitable propellant, and (3) a stabilizer comprising a wateraddition.

[0016] A suitable medicament or drug is one which is suitable foradministration by inhalation, the inhalation being used for oral andnasal inhalation therapy. Therapeutic categories of drugs or medicamentsinclude cardiovascular drugs, antiallergics, analgesics, brochodilators,antihistamines, antitussives, antifungals, antivirals, antibiotics, painmedicaments, anti-inflammatories, peptides, proteins and steroids. Ofcourse, not included within the medicaments of the subject invention arethe solvates of a beclomethasone compound.

[0017] Particularly suitable medicaments or drugs include albuterol(also known as salbutamol), atropine, budesonide, cromolyn, epinephrine,ephedrine, fentanyl, flunisolide, formoterol, ipratropium bromide,isoproterenol, pirbuterol, prednisolone, mometasone, triamcinoloneacetonide, salmeterol, amiloride, fluticasone, fluticasone esters, suchas phosphate, monohydrate and furoate,(−)4-amino-3,5-dichloro-α-[[[6(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzene-methanol.Also included are the suitable acid addition salts of the foregoingdrugs, their hydrates and their other solvates. In this regard, suitableacid addition salts include the salts obtained from inorganic acids,such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric andperchloric acids as well as organic acids such as tartaric, citric,acetic, succinic, maleic, fumaric and oxalic acids. Suitablepharmaceutically acceptable solvates include solvates with ethylactate,alkanes, ethers, alcohols and water.

[0018] A preferred embodiment of this invention are aerosol formulationswhich provide for a combination of at least two and most preferably notmore than four different medicaments such as cardiovascular drugs,antiallergenics, analgesics, bronchodilators, antihistamines,antitussives, antifungal, antiviral, antibiotics, pain medicaments,anti-inflammatories, peptides, proteins and steroids and of the use ofthese aerosol formulations to treat the disease states associated withthese medicaments. These medicaments and their use to treat a particulardisease state are well known to a practitioner of the art.

[0019] Especially preferred, are formulation which comprise combinationscomprising at least two different medicants, such as β2-adrenergicagonists, corticosteroids, anticholinergics and leucotriene modulators.Especially preferred are β2-adrenergic agonists, such as albuterol andformoterol and corticosteroids, such as mometasone, hydrocortisone,fludrocortisone, dexamethasone, prednisone, cortisone, aldosteronehemi-acetal, betamethasone, beclomethasone dipropionate, triamcinoloneacetonide, budesonide dipropionate, fluticasone propionate andflunisolide, anticholinergics, such as ipratropium bromide, histamineantagonists (mast cell modulators), such as cromolyn and non-steroidalantiinflamatory agents, such as acetaminophen or ibuprofen.

[0020] This invention includes the derivatives of the foregoingmedicaments. These derivatives include all the salt, ester, solvate andhydrate forms of the foregoing drugs as well as their geometric andoptical isomers, including their chiral forms. Such derivatives are wellknown to a practitioner in this art.

[0021] The leucotrienes contemplated in this invention are those whichare implicated as mediators of allergic and inflammatory responsesassociated with bronchial asthma and rheumatoid arthritis. Thismedicaments are known in the art to constrict dramatically the pulmonaryairways and small blood vessels. Thus, inhibitors or antagonists ofleucotrienes are effective mediators of the allergic responses typifiedby asthma and maybe used to treat bronchial asthma and other diseasesstates associated with inflammation of the airways.

[0022] The leucotriene modulators contemplated in this applicationinclude, but not limited to the following:

[0023] 1. Inhibitors or antagonists of lecotriene, including the PAFreceptor antagonists and 5-lipoxynase inhibitors, for example 2,5-diaryltetrahydrofurans, 2,5-diaryl tetrahydrothiophenes, 2,4-diaryltetrahydrofurans, 2,4-diaryl tetrahydrothiophenes, 1,3-diarylcyclopentanes, 2,4-diaryl pyrrolidines, and 2,5-diaryl pyrrolidines,triazolo(4,3-A)(1,4)benzodiazepines and thieno(3,2F)(1,2,4)triazolo(4,3-A)(1,4)diazepine compounds,6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines (see, U.S. Pat. Nos.5,856,323; 5,358,938; 4,959,361; and 3,987,052), including, bothoptically pure and racemates (U.S. Pat. No. 5,629,337). An example ofthis group of compounds is Zileuton® (Abbott Laboratories) and Acolate®(Merck).

[0024] 2. Chromone-2-carboxylic acid derivatives as antagonists of SRS-A(slow reacting substance of anaphylaxis (see, Samuelsson et al.,Department of Chemistry, Karolinska Institutet, Stockholm, Sweden, TIPS,227, May, 1980; J. Med. Chem. 20 371 (1977)), such as7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate(FPL 55712), which is a specific antagonist of SRS-A as well as astandard for evaluating other inhibitors;

[0025] 3. Aryloxyalkyloxy-and aralkyloxy-4-hydroxy-3-nitrocoumarins asantagonists of SRS-A and inhibitors of histamine release, (see. e.g.Buckle et al., J. Med. Chem. 22 158 (1979); U.S. Pat. No. 4,296,237;European Patent No. 0036663; U.S. Pat. No. 4,296,120; and U.S. Pat. No.4,296,129), as well as other compounds which act as inhibitors of SRS-Aincluding oxiranbutyric acid esters,3-hydroxy-4-substituted-3-pyrroline-2,5-diones orcarboxy-oxo-pyrrolidino)phenyl alkenamides and esters or(carboxyacylamino)phenyl alkenamides and esters, or the substitutedderivatives of these before mentioned compounds, including, but notlimited, to alkyl, hydroxy amino, dialkylamino, hydroxymethyl,aminomethyl, alkylaminomethyl or alkanoylaminomethyl of 1 to 12 carbonatoms; —CN, —CONH₂ or —CO₂M in which M is hydrogen, aryl, phenyl, ornaphthyl, cyclohexyl, cyclopentyl, or fluoromethoxy; or

[0026] 4. Antagonists and inhibitors of leukotriene includingN-o-tolylsulfonylbenzamide compounds.

[0027] All of the aforementional prior literature is expresslyincorporated by reference. These medicaments are known in the art totreat inflammatory diseases and include medicaments that block therelease, production, secretion, or any other biochemical actionarachidonic acid, prostaglandins and thromboxanes, or other leukotrienesthat participate in inflammatory reactions, exhibit chemotacticactivities, stimulate lysosomal enzyme release and act as importantfactors in the immediate hypersensitivity reaction.

[0028] Especially preferred medicaments include groups comprising[1-formyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-(hydroxycarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-((2-carboxyethyl)carbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-((2-tetrazolylethyl)carbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-(methylphenylcarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-(diphenylcarbamoyl)-5(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide;[1-carbamoyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,and[1-(pyrrolidine-carbonyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide.Also, pharmaceutically acceptable salts of these agents, includingaddition salts derived from organic or inorganic acids such ashydrochloric, hydrobromic, sulfuric, phosphoric, methane sulfonic,nitric, p-toluene sulfonic, acetic, citric, maleic, succinic acid andthe like. In addition, the compounds in their free carboxylic acid formmay be converted by standard techniques well-known to the practioner totheir corresponding alkali metal (e.g. sodium or potassium), alkalineearth metal (e.g. calcium or magnesium), ammonium or primary, secondaryand tertiary alkylamine salts, the latter containing from 1 to 6 carbonatoms in their alkyl moieties or a pharmaceutically acceptable saltthereof. These components are known in the literature and are described,for example in Brown et al., J. Med. Chem., vol. 35(13), pp. 2419 to2439 (1992) Jacobs et al., J. Med. Chem., vol. 37(9), pp. 1282 to 1297(1994); AU 646 587 Australia 3/1993; McFadden, E. R., Jr., Am Rev. Resp.Dis., vol. 147 pp. 1306-1310 (1993); Greenberger, P. A., Chest, vol. 101pp. 418S-421S (1992); Lipworth, B. J. Pharmacol. Ther., vol. 58 pp.173-209 (1993); Busse, W. W., Chest, vol. 104 pp. 1565-1571 (1993);Anonymous, Executive Summary: Guidelines for the Diagnosis andManagement of Asthma, Public Health Service, Publication 91-3042A, NIH,Bethesda, Md., pp. 1-44 (1991); Israel, E., and Drazen, J. M., N. Engl.J. Med., vol., 331 pp. 737-739 (1994); or Barnes, P. J., N. Engl. Med.,vol. 332 pp. 868-875 (1995). All these prior publications are expresslyincorporated by reference.

[0029] For purposes of the formulations of this invention, which areintended for inhalation into the lungs, the medicament or drug ispreferably micronized whereby a therapeutically effective amount orfraction (e.g., ninety percent or more) of the drug is particulate.Typically, the particles have a diameter of less than about 10 microns,and preferably less than about 5 microns, in order that the particlescan be inhaled into the respiratory tract and/or lungs.

[0030] The particulate medicament or drug is present in the inventiveformulations in a therapeutically effective amount, that is, an amountsuch that the drug can be administered as an aerosol, such as topically,or via oral or nasal inhalation, and cause its desired therapeuticeffect, typically preferred with one dose, or through several doses. Theparticulate drug is administered as an aerosol from a conventionalvalve, e.g., a metered dose valve.

[0031] The term “amount” as used herein refers to quantity or toconcentration as appropriate to the context. The amount of a drug thatconstitutes a therapeutically effective amount varies according tofactors such as the potency of the particular drug, the route ofadministration of the formulation, and the mechanical system used toadminister the formulation. A therapeutically effective amount of aparticular drug can be selected by those of ordinary skill in the artwith due consideration of such factors. Generally a therapeuticallyeffective amount will be from about 0.001 parts by weight to about 2parts by weight based on 100 parts by weight of the propellant.

[0032] A suitable propellant is selected. A suitable propellant is anyfluorocarbon, e.g. a 1-4 hydrogen containing flurocarbon(, such asCHF₂CHF₂, CF₃CH₂F, CH₂F₂CH₃ and CF₃CHFCF₃)), a perfluorocarbon, e.g. a1-4 carbon perfluorocarbon, (such as CF₃CF₃, CF₃CF₂CF₃); or any mixtureof the foregoing, having a sufficient vapor pressure to render themeffective as propellants. Some typical suitable propellants includeconventional chlorofluorocarbon (CFC) propellants such as mixtures ofpropellants 11, 12 and 114. Non-CFC propellants such as1,1,1,2-tetrafluoroethane (Propellant 134a),1,1,1,2,3,3,3-heptafluoropropane (Propellant 227) or mixtures thereofare preferred. The propellant is preferably present in an amountsufficient to propel a plurality of the selected doses of drug from anaerosol canister.

[0033] A suitable stabilizer is selected. A suitable stabilizer is a“water addition”. As used herein a “water addition” is an amount ofwater which (1) is added, either initially with other components of theaerosol formulation, e.g. medicament and propellant, or after the othercomponents, e.g. medicament, propellant, are combined and processed, (2)is in addition to the water which is always present and which developsduring processing and/or storage of the aerosol formulation, i.e.“developed” or “nascent” formulation water, and (3) is present in anamount which stabilizes the ordinarily unstable medicinal aerosoldispersion formulation having nascent formulation water.

[0034] An aerosol formulation preferably comprises the water addition inan amount effective to stabilize the formulation relative to anidentical formulation not containing the water addition, i.e. containingonly nascent formulation water, such that the drug does not settle,cream or flocculate after agitation so quickly as to preventreproducible dosing of the drug. Reproducible dosing can be achieved ifthe formulation retains a substantially uniform drug concentration forabout two or three seconds after agitation.

[0035] The particular amount of the water addition that constitutes aneffective amount is dependent upon the particular propellant and on theparticular drug used in the formulation. It is therefore not practicalto enumerate specific effective amounts for use with specificformulations of the invention, but such amounts can readily bedetermined by those skilled in the art with due consideration of thefactors set forth above. Generally, however, the water addition must bepresent in a formulation in an amount in excess of the concentration ofthe nascent formulation water. Such concentration of nascent formulationwater typically ranges up to 300 parts by weight per one million partsby weight of the total weight of the aerosol formulation. Accordingly,the water addition in excess of this nascent water concentrationtypically ranges from about 300 parts by weight to 2000 parts by weightper one million parts by weight of the total aerosol formulation weight.Most preferred is that the concentration of the water addition is from500 parts by weight to 700 parts by weight per one million parts byweight of the total weight of the medicinal aerosol formulation.

[0036] It is to be emphasized that this is an amount which exceeds theamount of nascent or developed formulation water. It is also to bestressed that this amount of water addition can be added and initiallycombined with the other components of the formulation, e.g. medicament,such as triamcinolone acetonide, and propellant, e.g.1,1,1,2-tetrahydrofluoroethane, or added to the resultant formulationafter these other components have been processed, e.g. prior to orsubsequent to storage.

[0037] It has surprisingly been found that the formulation of theinvention is stable without the necessity of employing a cosolvent, suchas ethanol, or surfactants. However, further components, such asconventional lubricants or surfactants, cosolvents, ethanol, etc., canalso be present in an aerosol formulation of the invention in suitableamounts readily determined by those skilled in the art. In this regard,reference is made to U.S. Pat. No. 5,225,183, which is incorporated byreference hereinto in its entirety.

[0038] A most preferred formulation comprises the medicament, thepropellant, the ethanol cosolvent and the water addition, for example,triamcinolone acetonide, budesonide, fluticasone, or mometasone,1,1,1,2-tetrafluoroethane, ethanol and the water addition.

[0039] Generally the formulations of the invention can be prepared bycombining (i) the drug in an amount sufficient to provide a plurality oftherapeutically effective doses; (ii) the water addition in an amounteffective to stabilize each of the formulations; (iii) the propellant inan amount sufficient to propel a plurality of doses from an aerosolcanister; and (iv) any further optional components e.g. ethanol as acosolvent; and dispersing the components. The components can bedispersed using a conventional mixer or homogenizer, by shaking, or byultrasonic energy. Bulk formulation can be transferred to smallerindividual aerosol vials by using valve to valve transfer methods,pressure filling or by using conventional cold-fill methods. It is notrequired that a stabilizer used in a suspension aerosol formulation besoluble in the propellant. Those that are not sufficiently soluble canbe coated onto the drug particles in an appropriate amount and thecoated particles can then be incorporated in a formulation as describedabove.

[0040] Aerosol canisters equipped with conventional valves, preferablymetered dose valves, can be used to deliver the formulations of theinvention. It has been found, however, that selection of appropriatevalve assemblies for use with aerosol formulations is dependent upon theparticular stabilizer and other adjuvants used (if any), on thepropellant, and on the particular drug being used. Conventional neopreneand buna valve rubbers used in metered dose valves for deliveringconventional CFC formulations often have less than optimal valvedelivery characteristics and ease of operation when used withformulations containing HFC-134a or HFC-227. Therefore certainformulations of the invention are preferably dispensed via a valveassembly wherein the diaphragm is made of a nitrile rubber such asDB-218 (American Gasket and Rubber, Schiller Park, Ill.) or an EPDMrubber such as Vistalon™ (Exxon), Royalene™ (UniRoyal), bunaEP (Bayer).Also suitable are diaphragms fashioned by extrusion, injection moldingor compression molding from a thermoplastic elastomeric material such asFLEXOMER™ GERS 1085 NT polyolefin (Union Carbide).

[0041] Conventional aerosol canisters, coated or uncoated, anodized orunanodized, e.g., those of aluminum, glass, stainless steel,polyethylene terephthalate, and coated canisters or cans with epon,epoxy, etc., can be used to contain a formulation of the invention.

[0042] The formulation of the invention can be delivered to therespiratory tract and/or lung by oral inhalation in order to effectbronchodilation or in order to treat a condition susceptible oftreatment by inhalation, e.g., asthma, chronic obstructive pulmonarydisease. The formulations of the invention can also be delivered bynasal inhalation in order to treat, e.g., allergic rhinitis, rhinitis,(local) or diabetes (systemic), or they can be delivered via topical(e.g., buccal) administration in order to treat, e.g., angina or localinfection.

What is claimed is:
 1. A method of stabilizing a medicinal aerosolformulation suspension formulation, comprising: (a) a therapeuticallyeffective amount of a particulate medicament; and (b) a fluidpropellant, which comprises: adding a stabilizer consisting of water ofaddition in an amount ranging from about 300 parts by weight to about2000 parts by weight to one million parts by total weight of theformulation whereby the medicament does not settle, cream or flocculateso quickly after agitation as to prevent reproducible dosing thereof. 2.The method as defined in claim 1, wherein the medicament is selectedfrom the group consisting of albuterol, atropine, budesonide, cromolyn,epinephrine, ephedrine, fentanyl, flunisolide, formoterol, ipratropiumbromide, isoproterenol, pirbuterol, prednisone, triamcinolone acetonide,salmeterol, amiloride, fluticasone,(−)4-amino-3,5-dichloro-α-[[[6(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzene-methanoland pharmaceutically acceptable esters, hydrates and solvates of theforegoing.
 3. The method as defined in claim 2, wherein the medicamentis budesonide, formoterol or fluticasone.
 4. The method in claim 1,wherein the medicament is fluticasone.
 5. The method in claim 1, whereinthe medicament are fluticasone and an anticholinergic agent.
 6. Themethod as defined in claim 1, wherein said propellant is selected fromthe group consisting of 1,1,1,2-tetrafluoroethane,1,1,1,2,3,3,3-heptafluoropropane or a mixture thereof..
 7. The method asdefined in claim 1, wherein said stabilizer is present in an amountranging from about 500 parts by weight to about 2000 parts weight basedon 1 million parts by total weight of the formulation.
 8. The method asdefined in claim 7 wherein said stabilizer is present in an amountranging from about 500 parts by weight to 700 parts by weight to onemillion parts by total weight of the formulation.
 9. The method asdefined in claim 1 the formulation is in an aerosol canister equippedwith a metered dose valve.
 10. A method as defined in claim 1 whereinsaid stabilizer is present in an amount ranging from about 500 parts byweight to about 2000 parts weight based on 1 million parts by totalweight of the formulation.
 11. The method as defined in claim 1 whereinsaid stabilizer is present in an amount ranging from 500 parts by weightto 700 parts by weight to one million parts by total weight of theformulation.
 12. A medicinal aerosol suspension formulation, whichconsists essentially of: (a) a therapeutically effective amount of aparticulate medicament which does not include a solvate of abeclomethasone compound; (b) a propellant; and (c) a stabilizerconsisting of water, in addition to nascent water present informulation, in an amount ranging from about 300 parts by weight toabout 2000 parts by weight to one million parts by total weight of theformulation; which is obtained by: (a) either: i.) combining saidmedicament, propellant and water; or ii.) combining said medicament andpropellant followed by the addition of water; and (b) dispersing themedicament propellant and water.
 13. The formulation as defined in claim1 wherein said solvate is beclomethasone dipropionate monohydrate. 14.The formulation as defined in claim 13 wherein the medicament isselected from the group consisting of albuterol, atropine, budesonide,cromolyn, epinephrine, ephedrine, fentanyl, flunisolide, formoterol,ipratropium bromide, isoproterenol, pirbuterol, prednisone,triamcinolone acetonide, salmeterol, amiloride, fluticasone, an ester offluticasone,(−)4-amino-3,5-dichloro-α-[[[6(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzene-methanoland pharmaceuticaly acceptable hydrates, salts and solvates of theforegoing.
 15. The formulation as defined in claim 14 wherein themedicament is budesonide, formoterol or fluticasone.
 16. The formulationas defined in claim 13 wherein the medicament is fluticasone.
 17. Theformulation as defined in claim 13 wherein the medicament is fluticasoneand an anticholinergic agent.
 18. The formulation as defined in claim 13wherein said propellant is selected from the group consisting of1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane and amixture thereof.
 19. The formulation as defined in claim 13 wherein saidstabilizer is present in an amount ranging from about 500 parts byweight to about 2000 parts weight based on 1 million parts by totalweight of the formulation.
 20. The formulation as defined in claim 19wherein said stabilizer is present in an amount ranging from 500 partsby weight to 700 parts by weight to one million parts by total weight ofthe formulation.
 21. A formulation according to claim 13 in an aerosolcanister equipped with a metered dose valve.
 22. A method of treating inan animal a condition capable of treatment by oral or nasal inhalation,which comprises, administering a formulation according to claim 12 tosaid animal by oral or nasal inhalation.
 23. A metered dose inhalercontaining a medicinal aerosol formulation, wherein the medicinalaerosol formulation is as defined in claim
 12. 24. The metered doseinhaler as defined in claim 23 wherein the medicament is fluticasone orfluticasone and an anticholinergic agent.
 25. The metered dose inhaleras defined in claim 23 wherein the medicament is selected from the groupconsisting of albuterol, atropine, budesonide, cromolyn, epinephrine,ephedrine, fentanyl, flunisolide, formoterol, ipratropium bromide,isoproterenol, pirbuterol, prednisone, triamcinolone acetonide,salmeterol, amiloride, fluticasone, an ester of fluticasone,(−)4-amino-3,5-dichloro-α-[[[6(2-pyridinyl)ethoxyl]hexyl]amino]methyl]benzene-methanoland pharmaceuticaly acceptable hydrates, salts and solvates of theforegoing.
 26. The metered dose inhaler as defined in claim 23 whereinthe propellant is selected from the group consisting of1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane and amixture thereof.
 27. The metered dose inhaler as defined in claim 26wherein said medicament comprises triamcinolone acetonide.
 28. Themetered dose inhaler as defined in claim 27 wherein said stabilizer ispresent in an amount ranging from 500 parts by weight to 700 parts byweight per one million parts by weight of the medicinal aerosolformulation.
 29. A medicinal aerosol formulation, which consistsessentially of: (a) a therapeutically effective amount of a particulatemedicament; other than a hydrate of beclomethasone compound; (b) apropellant; (c) a cosolvent; and (d) a stabilizer consisting of water,in addition to nascent water present in formulation, in an amountranging from about 300 parts by weight to about 2000 parts by weight toone million parts by total weight of the formulation; which is obtainedby: (a) either: i.) combining said medicament, propellant and water; orii.) combining said medicament and propellant and cosolvent followed bythe addition of water; and (b) dispersing the medicament propellant,cosolvent and water.
 30. The formulation as defined in claim 29 whereinsaid medicament is selected from the group consisting of albuterol,atropine, budesonide, cromolyn, epinephrine, ephedrine, fentanyl,flunisolide, formoterol, ipratropium bromide, isoproterenol, pirbuterol,prednisone, triamcinolone acetonide, salmeterol, amiloride, fluticasone,(−)4-amino-3,5-dichloro-α-[[[6(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzene-methanoland pharmaceuticaly acceptable salts, esters, hydrates, and solvates ofthe foregoing.
 31. The formulation as defined in claim 29 wherein saidmedicament is selected from the group consisting of albuterol, atropine,budesonide, cromolyn, epinephrine, ephedrine, fentanyl, flunisolide,formoterol, ipratropium bromide, isoproterenol, pirbuterol, prednisone,triamcinolone acetonide, salmeterol, amiloride, fluticasone,(−)4-amino-3,5-dichloro-α[[[6(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzene-methanoland pharmaceuticaly acceptable esters and solvates of the foregoing. 32.The formulation as defined in claim 29 wherein said medicament comprisestriamcinolone acetonide, budesonide, fomoterol, or fluticasone.
 33. Theformulation as defined in claim 29 wherein said cosolvent is ethanol.34. The formulation as defined in claim 29 wherein said stabilizer ispresent in an amount ranging from 500 parts by weight to 2000 parts byweight based on 1 million parts by total weight of the formulation. 35.The formulation as defined in claim 29 wherein said stabilizer ispresent in an amount ranging from 500 parts by weight to 700 parts byweight to one million parts by total weight of the formulation.
 36. Amethod of treating in an animal a condition capable of treatment by oralor nasal inhalation, which comprises, administering a formulationaccording to claim 29 to said animal by oral or nasal inhalation.
 37. Aformulation according to claim 29 in an aerosol canister equipped with ametered dose valve.
 38. A metered dose inhaler containing a medicinalaerosol formulation, wherein the medicinal aerosol formulation is asdefined in claim
 29. 39. The metered dose inhaler as defined in claim 38wherein the drug is selected from the group consisting of albuterol,atropine, budesonide, cromolyn, epinephrine, ephedrine, fentanyl,flunisolide, formoterol, ipratropium bromide, isoproterenol, pirbuterol,prednisone, triamcinolone acetonide, salmeterol, amiloride, fluticasone,(−)4-amino-3,5-dichloro-α-[[[6(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzene-methanoland pharmaceuticaly acceptable hydrates, salts, and solvates of theforegoing.
 40. The metered dose inhaler as defined in claim 39 whereinthe propellant is selected from the group consisting of1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane or a mixturethereof.
 41. The metered dose inhaler as defined in claim 40 whereinsaid medicament triamcinolone acetonide, budesonide, budesonide, orfluticasone, and the cosolvent is ethanol.
 42. The metered dose inhaleras defined in claim 41 wherein said stabilizer is present in an amountranging from 500 parts by weight to 700 parts by weight per one millionparts by weight of the medicinal aerosol formulation.
 43. A medicinalaerosol formulation, which consists essentially of: (a) atherapeutically effective amount of a particulate medicament; notincluding a solvate of a beclomethasone compound. (b) a propellant; (c)optionally, a cosolvent; and (d) a stabilizer consisting of water, inaddition to nascent water present in formulation, in an amount rangingfrom about 300 parts by weight to about 2000 parts by weight to onemillion parts by total weight of the formulation.
 44. The metered doseinhaler as defined in claim 43 wherein the medicament is selected fromthe group consisting of albuterol, atropine, budesonide, cromolyn,epinephrine, ephedrine, fentanyl, flunisolide, formoterol, ipratropiumbromide, isoproterenol, pirbuterol, prednisone, triamcinolone acetonide,salmeterol, amiloride, fluticasone,(−)4-amino-3,5-dichloro-α-[[[6(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzene-methanoland pharmaceuticaly acceptable hydrates, salts, and solvates of theforegoing and the propellent is selected from the group consisting of1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane or a mixturethereof.
 45. The formulation as defined in claim 44 wherein a cosolventis present.
 46. The formulation as defined in claim 44 wherein themedicament is tramcinolone acetonide, budesonide, formoterol orfluticasone.
 47. A medicinal aerosol formulations, which consistsessentially of: a) a therapeutically effective amount of a combinationof at least two different particulate medicaments which does not includea solvate of a beclomethasone compound; b) a propellant; and c) astabilizer consisting of water, in addition to nascent water present informulation, in an amount ranging from about 300 parts by weight toabout 2000 parts by weight to one million parts by total weight of theformulation; which is obtained by a) either: i) combining saidmedicaments, propellant and water; or ii) combining said medicaments andpropellant followed by the addition of water; and b) dispersing themedicaments propellant and water.
 48. The formulation as defined inclaim 48, wherein one medicament is selected from the group consistingof albuterol, atropine, budesonide, cromolyn, epinephrine, ephedrine,fentanyl, fluinisolide, formoterol, ipratropium bromide, isoproterenol,pirbuterol, prednisone, triamcinolone acetonide, salmeterol, amiloride,fluticasone,(−)4-amino-3,5-dichloro-α-[[[6(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzene-methanoland pharmaceuticaly acceptable hydrates, salts, and solvates of theforegoing.
 49. The formulation as defined in claim 47, wherein themedicaments in the combination are selected from the group consisting ofβ-2 adrenergic agonists, corticosteroids, anticholinergics, histamineantagonists, non-steroidal antiinflammatory agents and leucotrienemodulators.
 50. The formulation as defined in claim 49, wherein the β-2adrenergic agonists are albuterol, formoterol or the pharmaceuticallyacceptable salts, esters or the optical or geometric isomers of theforegoing.
 51. The formulation as defined in claim 49, wherein thecorticosteroids are selected from the group consisting of monetasone,hydrocortisone, fludrocortisone, dexamethasone, prednisone, cortisone,aldosterone hemi-acetal, betametasone, beclomethasone dipropionate,triamcinolone acetonide, budesonide, dipropionate, fluticasone,flunisolide and the pharmaceutically acceptable salts, esters, hydrates,solvates and optical or geometric isomers of the foregoing.
 52. Theformulation as defined in claim 49, wherein the anticholinergic iscromolyn, or the pharmaceutically acceptable salts or esters of theforegoing.
 54. The formulation as defined in claim 49, wherein theleucotriene modulator is selected from the group consisting of[[1-formyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxyl-N-o-tolylsulfonylbenzamide,[1-(hydroxycarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-((2-carboxyethyl)carbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-((2-tetrazolylethyl)carbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-(methylphenylcarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide;[1-(diphenylcarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide;[1-carbamoyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-(pyrrolidine-carbonyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,the pharmaceutically acceptable salts of the foregoing and mixtures ofany of the foregoing medicaments.
 54. The formulation as defined inclaim 47, wherein the combination comprises a corticosteroid and a β-2adrenergic agonist.
 55. The formulation as defined in claim 47, whereinthe combination comprises a corticosteroid and an anticholinergic agent.56. The formulation as defined in claim 47, wherein the combinationcomprises a corticosteroid and a leucotriene modulator.
 57. Theformulation as defined in claim 47, wherein the combination comprises acorticosteroid, a β-2 adrenergic agonist and a leucotriene modulator.58. The formulation as defined in claim 54, wherein the corticosteroidis fluiticasone or fluticasone proprionate.
 59. The formulation asdefined in claim 47 wherein the combination comprises a β-2 adrenergicagonist or a leucotreine modulator or a β-2 adrenergic agonist and ananticholinergic.
 60. The formulation as defined in claim 47, wherein thecombination comprises a non-steroidal antiinflamatory or a histamineantagonist.
 61. The formulation as defined in claim 47, wherein saidpropellant is selected from the group consisting of1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane or a mixturethereof.
 62. The formulation as defined in claim 47, wherein saidstabilizer is present in an amount ranging from about 500 parts byweight to about 2000 parts weight based on 1 million parts by totalweight of the formulation.
 63. The formulation as defined in claim 61,wherein said stabilizer is present\in an amount ranging from 500 partsby weight to 700 parts by weight to one million parts by total weight ofthe formulation.
 64. A formulation according to claim 47, in an aerosolcanister equipped with a metered does valve.
 65. A method of treating inan animal a condition capable of treatment by oral or nasal inhalation,which comprises, administering a formulation according to claim 47 tosaid animal by oral or nasal inhalation.
 66. A metered dose inhalercontaining medicinal aerosol formulation, wherein the medicinal aerosolformulation is as defined in claim
 47. 67. The metered dose inhaler asdefined in claim 66, wherein the propellant is selected from the groupconsisting of 1,1,1,2-tetrafluoroethane,1,1,1,2,3,3,3-heptafluoropropane and a mixture thereof.
 68. The metereddose inhaler as defined in claim 66, wherein said stabilizer is presentin an amount ranging from 500 parts by weight to 700 parts be weight perone million parts by weight of the medicinal aerosol formulation.
 69. Amedicinal aerosol formulation, which consists essentially of: a) atherapeutically effective amount of a particulate medicament, notincluding a solvate of a beclomethasone compound. b) a propellant; c) acosolvent; and d) a stabilizer consisting of water, in addition tonascent water present in formulation, in an amount ranging from about300 parts by weight to about 2000 parts by weight to one million partsby total weight of the formulation; which is obtained by a) either: i)combining said medicament, propellant, cosolvent and water; or ii)combining said medicament, propellant, and cosolvent followed by theaddition of water; and iii) dispersing the medicament propellant,cosolvent and water.
 70. The formulation as defined in claim 69, whereinone of the medicaments is selected from the group consisting ofalbuterol, atropine, budesonide, cromolyn, epinephrine, ephedrine,fentanyl, flunisolide, formoterol, ipratropium bromide, isoproterenol,pirbuterol, prednisone, triamcinolone, acetonide, salmeterol, amiloride,fluticasone,(−)4-amino-3,5-dichloro-α[[[6(2-pyridinyl-ethoxy]hexyl]amino]methyl]benzene-methanoland pharmaceutically acceptable salts, esters, hydrates and solvates ofthe foregoing.
 71. The formulation as defined in claim 69, wherein themedicaments in the combination are selected from the group consisting ofβ-2 adrenergic agonists, corticosteroids, anticholinergics, histamineantagonists, non-steroidal antiinflammatory agents and leucotrienemodulators.
 72. The formulation as defined in claim 71, wherein themedicaments in the combination are selected from the group consisting ofβ-2 adrenergic agonists, corticosteroids, anticholinergics, histamineantagonists, non-steroidal antiinflammatory agents and leucotrienemodulators.
 73. The formulation as defined in claim 69, wherein themedicaments in the combination are selected from the group consisting ofβ-2 adrenergic agonists, corticosteroids, anticholinergics, histamineantagonists, non-steroidal antiinflammatory agents and leucotrienemodulators.
 74. The formulation as defined in claim 71, wherein theanticholinergic is cromolyn, or the pharmaceutically acceptable salts oresters of the foregoing.
 75. The formulation as defined in claim 71,wherein the anticholinergic is cromolyn, or the pharmaceuticallyacceptable salts or esters of the foregoing.
 76. The formulation asdefined in claim 71, wherein the anticholinergic is cromolyn, or thepharmaceutically acceptable salts or esters of the foregoing.
 77. Theformulation as defined in claim 71, wherein the anticholinergic iscromolyn, or the pharmaceutically acceptable salts or esters of theforegoing
 78. The formulation as defined in claim 69, wherein theleucotriene modulator is selected from the group consisting of[[1-formyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxyl-N-o-tolylsulfonylbenzamide,[1-(hydroxycarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-((2-carboxyethyl)carbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-((2-tetrazolylethyl)carbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-(methylphenylcarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide;[1-(diphenylcarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide;[1-carbamoyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-(pyrrolidine-carbonyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,the pharmaceutically acceptable salts of the foregoing and mixtures ofany of the foregoing medicaments.
 79. The formulation as defined inclaim 69, wherein the combination comprises a corticosteroid and a β-2adrenergic agonist.
 80. The formulation as defined in claim 69, whereinthe combination comprises a corticosteroid and an anticholinergic agent.81. The formulation as defined in claim 69, wherein the combinationcomprises a corticosteroid and a leucotriene modulator.
 82. Theformulation as defined in claim 69, wherein the combination comprises acorticosteroid, a β-2 adrenergic agonist and a leucotriene modulator.83. The formulation as defined in claim 79, wherein the corticosteroidis fluiticasone or fluticasone proprionate.
 84. The formulation asdefined in claim 69, wherein the combination comprises a β-2 adrenergicagonist or a leucotreine modulator or a β-2 adrenergic agonist and ananticholinergic.
 85. The formulation as defined in claim 69, wherein thecombination comprises a non-steroidal antiinflamatory or a histamineantagonist.
 86. The formulation as defined in claim 69, whereincosolvent is ethanol.
 87. The formulation as defined in claim 69,wherein said stabilizer is present in an amount ranging from about 500parts by weight to about 2000 parts weight based on 1 million parts bytotal weight of the formulation.
 88. The formulation as defined in claim69, wherein said stabilizer is present in an amount ranging from 500parts by weight to 700 parts by weight to one million parts by totalweight of the formulation.
 89. A method of treating in an animal acondition capable of treatment of oral or nasal inhalation, whichcomprises, administering a formulation according to claim 69 to saidanimal by oral or nasal inhalation.
 90. A metered dose inhalercontaining a medicinal aerosol formulation, wherein the medicinalaerosol formulation is as defined in claim
 69. 91. The metered doseinhaler as defined in claim 66, wherein the propellant is selected fromthe group consisting of 1,1,1,2-tetrafluoroethane,1,1,1,2,3,3,3-heptafluoropropane and a mixture thereof.
 92. The metereddose inhaler as defined in claim 69, wherein said stabilizer is presentin an amount ranging from 500 parts by weight to 700 parts by weight perone million parts by weight of the medicinal aerosol formulation.
 93. Amedicinal aerosol formulation, which consists essentially of: a)therapeutically effective amount of a combination of at least twodifferent particulate medicaments, not including a solvate of abeclomethasone compound; b) a propellant; c) optionally, a cosolvent;and d) a stabilizer consisting of water, in addition to nascent waterpresent in formulation, in an amount ranging from about 300 parts byweight to about 2000 parts by weight to one million parts by totalweight of the formulation.
 94. A medicinal aerosol formulation asdefined in claim 93, wherein one of the medicaments is selected form thegroup consisting of albuterol, atropine, budesonide, cromolyn,epinephrine, ephedrine, fentanyl, flunisolide, formoterol, ipratropiumbromide, isoproterenol, pirbuterol, prednisone, triamcinolone acetonide,salmeterol, amiloride, fluticasone, (−)4-amino-3,5-dicholoroα-[[[6(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzene-methanol andpharmaceutically acceptable, salts, esters, hydrates, and solvates ofthe foregoing and the propellent is selected from the group consistingof 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane and amixture therefore.
 95. The formulation as defined in claim 93, wherein acosolvent is present.
 96. The formulation as defined in claim 93,wherein the medicaments in the combination are selected from the groupconsisting of β-2 adrenergic agonists, corticosteroids,anticholinergics, histamine antagonists, non-steroidal antiinflammatoryagents and leucotriene modulators.
 97. The formulation as defined inclaim 96, wherein the β-2 adrenergic agonists are albuterol, formoterolor the pharmaceutically acceptable salts, esters or the optical orgeometric isomers of the foregoing.
 98. The formulation as defined inclaim 96, wherein the corticosteroids are selected from the groupconsisting of monetasone, hydrocortisone, fludrocortisone,dexamethasone, prednisone, cortisone, aldosterone hemi-acetal,betametasone, beclomethasone dipropionate, triamcinolone acetonide,budesonide, dipropionate, fluticasone, flunisolide and thepharmaceutically acceptable salts, esters, hydrates, solvates andoptical or geometric isomers of the foregoing.
 99. The formulation asdefined in claim 96, wherein the anti-cholinergic is cromolyn, or thepharmaceutically acceptable salts or esters of the foregoing.
 100. Theformulation as defined in claim 96, wherein the leucotriene modulator isselected from the group consisting of[[1-formyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxyl-N-o-tolylsulfonylbenzamide,[1-(hydroxycarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-((2-carboxyethyl)carbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-((2-tetrazolylethyl)carbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-(methylphenylcarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide;[1-(diphenylcarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide;[1-carbamoyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-(pyrrolidine-carbonyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,the pharmaceutically acceptable salts of the foregoing and mixtures ofany of the foregoing medicaments.
 101. The formulation as defined inclaim 93, wherein the combination comprises a corticosteroid and a β-2adrenergic agonist.
 102. The formulation as defined in claim 93, whereinthe combination comprises a corticosteroid and an anticholinergic agent.103. The formulation as defined in claim 93, wherein the combinationcomprises a corticosteroid and a leucotriene modulator.
 104. Theformulation as defined in claim 93, wherein the combination comprises acorticosteroid, a β-2 adrenergic agonist and a leucotriene modulator.105. The formulation as defined in claim 102, wherein the corticosteroidis fluiticasone or fluticasone proprionate.
 106. The formulation asdefined in claim 93 wherein the combination comprises a β-2 adrenergicagonist or a leucotreine modulator or a β-2 adrenergic agonist and ananticholinergic.
 107. The formulation as defined in claim 93, whereinthe combination comprises a non-steroidal antiinflamatory or a histamineantagonist.
 108. A method of treating in an animal a condition capableof treating by oral or nasal inhalation, which comprises administering aformulation according to claim 93 to said animal by oral or nasalinhalation.
 109. A metered dose inhaler containing a medicinal aerosolformulation, wherein the medicinal aerosol formulation is as defined inclaim
 93. 110. The metered dose inhaler as defined in claim 109, whereinthe propellant is selected from the group consisting of1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3-heptafluoropropane and a mixturethereof.
 111. A method of stabilizing a medicinal aerosol suspensionformulation which consists essentially of: a) a therapeuticallyeffective amount of a combination of at least two different particulatemedicaments; which does not include a solvate of a beclomethasonecompound; and b) a propellant, which comprises, adding to theformulation a stabilizer consisting essentially of a water additionpresent in the formulation in an amount ranging from about 300 parts byweight to about 2000 parts by weight to one million parts by totalweight of the formulation; which is obtained by a) either: i) combiningsaid medicaments, propellant and water; or ii) combining saidmedicaments and propellant followed by the addition of water; and b)dispersing the medicaments propellant and water and which prevents themedicament from settling creaming or flocculating so quickly afteragitation as to prevent reproducible dosing thereof.
 112. The method asdefined in claim 111 wherein one medicament is selected from the groupconsisting of albuterol, atropine, budesonide, cromolyn, epinephrine,ephedrine, fentanyl, flunisolide, formoterol, ipratropium bromide,isoproterenol, pirbuterol, prednisone, triamcinolone acetonide,salmeterol, amiloride, fluticasone, an ester of fluticasone,(−)4-amino-3,5-dichloro-α-[[[6(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzene-methanoland pharmaceutically acceptable esters and solvates of the foregoing.113. The method as defined in claim 111 wherein the medicaments in thecombination are selected from the group consisting of β-2 adrenergicagonists, corticosteroids, anticholinergics, histamine antagonists,non-steroidal antiinflammatory agents and leucotriene modulators. 114.The method as defined in claim 113, wherein the β-2 adrenergic agonistsare albuterol, formoterol or the pharmaceutically acceptable salts,esters or the optical or geometric isomers of the foregoing.
 115. Themethod as defined in claim 113, wherein the corticosteroids are selectedfrom the group consisting of monetasone, hydrocortisone,fludrocortisone, dexamethasone, prednisone, cortisone, aldosteronehemi-acetal, betametasone, beclomethasone dipropionate, triamcinoloneacetonide, budesonide, dipropionate, fluticasone, flunisolide and thepharmaceutically acceptable salts, esters, hydrates, solvates andoptical or geometric isomers of the foregoing.
 116. The method asdefined in claim 113, wherein the anticholinergic is cromolyn, or thepharmaceutically acceptable salts or esters of the foregoing.
 117. Themethod as defined in claim 113, wherein the leucotriene modulator isselected from the group consisting of[[1-formyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-(hydroxycarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-((2-carboxyethyl)carbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-((2-tetrazolylethyl)carbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-(methylphenylcarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide;[1-(diphenylcarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide;[1-carbamoyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-(pyrrolidine-carbonyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,the pharmaceutically acceptable salts of the foregoing and mixtures ofany of the foregoing medicaments.
 118. The method as defined in claim111, wherein the combination comprises a corticosteroid and a β-2adrenergic agonist.
 119. The method as defined in claim 111, wherein thecombination comprises a corticosteroid and an anticholinergic agent.120. The method as defined in claim 111, wherein the combinationcomprises a corticosteroid and a leucotriene modulator.
 121. The methodas defined in claim 111, wherein the combination comprises acorticosteroid, a β-2 adrenergic agonist and a leucotriene modulator.122. The method as defined in claim 118, wherein the corticosteroid isfluiticasone or fluticasone proprionate.
 123. The method as defined inclaim 111 wherein the combination comprises a β-2 adrenergic agonist ora leucotreine modulator or a β-2 adrenergic agonist and ananticholinergic.
 124. The method as defined in claim 111, wherein thecombination comprises a non-steroidal antiinflamatory or a histamineantagonist.
 125. The method as defined in claim 111, wherein saidpropellant is selected from the group consisting of1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane or a mixturethereof.
 126. The method as defined in claim 111, wherein saidstabilizer is present in an amount ranging from about 500 parts byweight to about 2000 parts weight based on 1 million parts by totalweight of the formulation.
 127. The method as defined in claim 125,wherein said stabilizer is present\in an amount ranging from 500 partsby weight to 700 parts by weight to one million parts by total weight ofthe formulation.
 128. A method of stabilizing a medicinal aerosolsuspension which consists essentially of: a) a therapeutically effectiveamount of a particulate mixture of medicaments not including a solvateof a beclomethasone compound, where at least one of the medicaments isselected from the group consisting of medicaments is selected from thegroup consisting of albuterol, atropine, budesonide, cromolyn,epinephrine, ephedrine, fentanyl, flunisolide, formoterol, ipratropiumbromide, isoproterenol, pirbuterol, prednisone, triamcinolone acetonide,salmeterol, amiloride, fluticasone,(−)4-amino-3,5-dichloro-α-[[[6(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzene-methanoland pharmaceuticaly acceptable salts, esters, hydrates and solvates ofthe foregoing b) a propellant; c) a cosolvent; which comprises adding tothe mixture d) a stabilizer consisting of water, in addition to nascentwater present in formulation, in an amount ranging from about 300 partsby weight to about 2000 parts by weight to one million parts by totalweight of the formulation; which is obtained by a) either: i) combiningsaid medicament, propellant, cosolvent and water; or ii) combining saidmedicament, propellant, and cosolvent followed by the addition of water;and iii) dispersing the medicament propellant, cosolvent and water. 129.The method as defined in claim 128, wherein the medicaments in thecombination are selected from the group consisting of β-2 adrenergicagonists, corticosteroids, anticholinergics, histamine antagonists,non-steroidal antiinflammatory agents and leucotriene modulators. 130.The method as defined in claim 129, wherein the medicaments in thecombination are selected from the group consisting of β-2 adrenergicagonists, corticosteroids, anticholinergics, histamine antagonists,non-steroidal antiinflammatory agents and leucotriene modulators. 131.The method as defined in claim 128, wherein the medicaments in thecombination are selected from the group consisting of β-2 adrenergicagonists, corticosteroids, anticholinergics, histamine antagonists,non-steroidal antiinflammatory agents and leucotriene modulators. 132.The method as defined in claim 129, wherein the anticholinergic iscromolyn, or the pharmaceutically acceptable salts or esters of theforegoing.
 133. The method as defined in claim 129, wherein theanticholinergic is cromolyn, or the pharmaceutically acceptable salts oresters of the foregoing.
 134. The method as defined in claim 129,wherein the anticholinergic is cromolyn, or the pharmaceuticallyacceptable salts or esters of the foregoing.
 135. The method as definedin claim 129, wherein the anticholinergic is cromolyn, or thepharmaceutically acceptable salts or esters of the foregoing
 136. Themethod as defined in claim 128, wherein the leucotriene modulator isselected from the group consisting of[[1-formyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxyl-N-o-tolylsulfonylbenzamide,[1-(hydroxycarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-((2-carboxyethyl)carbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-((2-tetrazolylethyl)carbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-(methylphenylcarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide;[1-(diphenylcarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide;[1-carbamoyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-(pyrrolidine-carbonyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,the pharmaceutically acceptable salts of the foregoing and mixtures ofany of the foregoing medicaments.
 137. The method as defined in claim128, wherein the combination comprises a corticosteroid and a 13-2adrenergic agonist.
 139. The method as defined in claim 128, wherein thecombination comprises a corticosteroid and an anticholinergic agent.140. The method as defined in claim 128, wherein the combinationcomprises a corticosteroid and a leucotriene modulator.
 141. The methodas defined in claim 137, wherein the corticosteroid is fluiticasone orfluticasone proprionate.
 142. The method as defined in claim 128,wherein the combination comprises a β-2 adrenergic agonist or aleucotreine modulator or a 62 -2 adrenergic agonist and ananticholinergic.
 143. The method as defined in claim 128, wherein thecombination comprises a non-steroidal antiinflamatory or a histamineantagonist.
 144. The method as defined in claim 128, wherein cosolventis ethanol.
 145. The method as defined in claim 128, wherein saidstabilizer is present in an amount ranging from about 500 parts byweight to about 2000 parts weight based on 1 million parts by totalweight of the formulation.
 146. The method as defined in claim 128,wherein said stabilizer is present in an amount ranging from 500 partsby weight to 700 parts by weight to one million parts by total weight ofthe formulation.
 147. A method of stabilizing a medicinal aerosolformulation, which consists essentially of: a) therapeutically effectiveamount of a combination of at least two different particulatemedicaments, not including a solvate of a beclonethasone compound b) apropellant; c) optionally, a cosolvent; which comprises, adding astabilizer consisting of water, in addition to nascent water present informulation, in an amount ranging from about 300 parts by weight toabout 2000 parts by weight to one million parts by total weight of theformulation.
 148. A method as defined in claim 147, wherein one of themedicaments is selected form the group consisting of albuterol,atropine, budesonide, cromolyn, epinephrine, ephedrine, fentanyl,flunisolide, formoterol, ipratropium bromide, isoproterenol, pirbuterol,prednisone, triamcinolone acetonide, salmeterol, amiloride, fluticasone,(−)4-amino-3,5-dicholoroα-[[[6(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzene-methanol andpharmaceutically acceptable, salts, esters, hydrates, and solvates ofthe foregoing and the propellent is selected from the group consistingof 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane and amixture therefore.
 149. The method as defined in claim 147, wherein acosolvent is present.
 150. The method as defined in claim 147, whereinthe medicaments in the combination are selected from the groupconsisting of 62 -2 adrenergic agonists, corticosteroids,anticholinergics, histamine antagonists, non-steroidal antiinflammatoryagents and leucotriene modulators.
 151. The method as defined in claim148, wherein the β-2 adrenergic agonists are albuterol, formoterol orthe pharmaceutically acceptable salts, esters or the optical orgeometric isomers of the foregoing.
 152. The method as defined in claim148, wherein the corticosteroids are selected from the group consistingof monetasone, hydrocortisone, fludrocortisone, dexamethasone,prednisone, cortisone, aldosterone hemi-acetal, betametasone,beclomethasone dipropionate, triamcinolone acetonide, budesonide,dipropionate, fluticasone, flunisolide and the pharmaceuticallyacceptable salts, esters, hydrates, solvates and optical or geometricisomers of the foregoing.
 153. The method as defined in claim 148,wherein the anti-cholinergic is cromolyn, or the pharmaceuticallyacceptable salts or esters of the foregoing.
 154. The method as definedin claim 148, wherein the leucotriene modulator is selected from thegroup consisting of[[1-formyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxyl-N-o-tolylsulfonylbenzamide,[1-(hydroxycarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-((2-carboxyethyl)carbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-((2-tetrazolylethyl)carbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-(methylphenylcarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide;[1-(diphenylcarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide;[1-carbamoyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,[1-(pyrrolidine-carbonyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide,the pharmaceutically acceptable salts of the foregoing and mixtures ofany of the foregoing medicaments.
 155. The method as defined in claim147, wherein the combination comprises a corticosteroid and a β-2adrenergic agonist.
 156. The method as defined in claim 147, wherein thecombination comprises a corticosteroid and an anticholinergic agent.157. The method as defined in claim 147, wherein the combinationcomprises a corticosteroid and a leucotriene modulator.
 158. The methodas defined in claim 147, wherein the combination comprises acorticosteroid, a β-2 adrenergic agonist and a leucotriene modulator.159. The method as defined in claim 155, wherein the corticosteroid isfluiticasone or fluticasone proprionate.
 160. The method as defined inclaim 147 wherein the combination comprises a β-2 adrenergic agonist ora leucotreine modulator or a β-2 adrenergic agonist and ananticholinergic.
 161. The method as defined in claim 147, wherein thecombination comprises a non-steroidal antiinflamatory or a histamineantagonist.